Charged Particles in a 2+1 Curved Background

The coupling to a 2+1 background geometry of a quantized charged test particle in a strong magnetic field is analyzed. Canonical operators adapting to the fast and slow freedoms produce a natural expansion in the inverse square root of the magnetic field strength. The fast freedom is solved to the second order. At any given time, space is parameterized by a couple of conjugate operators and effectively behaves as the `phase space' of the slow freedom. The slow Hamiltonian depends on the magnetic field norm, its covariant derivatives, the scalar curvature and presents a peculiar coupling with the spin-connection.Comment: 22 page

230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Costa, K. M., Hayes, C. T., Anderson, R. F., Pavia, F. J., Bausch, A., Deng, F., Dutay, J., Geibert, W., Heinze, C., Henderson, G., Hillaire-Marcel, C., Hoffmann, S., Jaccard, S. L., Jacobel, A. W., Kienast, S. S., Kipp, L., Lerner, P., Lippold, J., Lund, D., Marcantonio, F., McGee, D., McManus, J. F., Mekik, F., Middleton, J. L., Missiaen, L., Not, C., Pichat, S., Robinson, L. F., Rowland, G. H., Roy-Barman, M., Alessandro, Torfstein, A., Winckler, G., & Zhou, Y. 230 Th normalization: new insights on an essential tool for quantifying sedimentary fluxes in the modern and quaternary ocean. Paleoceanography and Paleoclimatology, 35(2), (2020): e2019PA003820, doi:10.1029/2019PA003820.230Th normalization is a valuable paleoceanographic tool for reconstructing high‐resolution sediment fluxes during the late Pleistocene (last ~500,000 years). As its application has expanded to ever more diverse marine environments, the nuances of 230Th systematics, with regard to particle type, particle size, lateral advective/diffusive redistribution, and other processes, have emerged. We synthesized over 1000 sedimentary records of 230Th from across the global ocean at two time slices, the late Holocene (0–5,000 years ago, or 0–5 ka) and the Last Glacial Maximum (18.5–23.5 ka), and investigated the spatial structure of 230Th‐normalized mass fluxes. On a global scale, sedimentary mass fluxes were significantly higher during the Last Glacial Maximum (1.79–2.17 g/cm2kyr, 95% confidence) relative to the Holocene (1.48–1.68 g/cm2kyr, 95% confidence). We then examined the potential confounding influences of boundary scavenging, nepheloid layers, hydrothermal scavenging, size‐dependent sediment fractionation, and carbonate dissolution on the efficacy of 230Th as a constant flux proxy. Anomalous 230Th behavior is sometimes observed proximal to hydrothermal ridges and in continental margins where high particle fluxes and steep continental slopes can lead to the combined effects of boundary scavenging and nepheloid interference. Notwithstanding these limitations, we found that 230Th normalization is a robust tool for determining sediment mass accumulation rates in the majority of pelagic marine settings (>1,000 m water depth).We thank Zanna Chase and one anonymous reviewer for valuable feedback. K. M. C. was supported by a Postdoctoral Scholarship at WHOI. L. M. acknowledges funding from the Australian Research Council grant DP180100048. The contribution of C. T. H., J. F. M., and R. F. A. were supported in part by the U.S. National Science Foundation (US‐NSF). G. H. R. was supported by the Natural Environment Research Council (grant NE/L002434/1). S. L. J. acknowledges support from the Swiss National Science Foundation (grants PP002P2_144811 and PP00P2_172915). This study was supported by the Past Global Changes (PAGES) project, which in turn received support from the Swiss Academy of Sciences and the US‐NSF. This work grew out of a 2018 workshop in Aix‐Marseille, France, funded by PAGES, GEOTRACES, SCOR, US‐NSF, Aix‐Marseille Université, and John Cantle Scientific. All data are publicly available as supporting information to this document and on the National Center for Environmental Information (NCEI) at https://www.ncdc.noaa.gov/paleo/study/28791

Gender, risk and the Wall Street alpha male

From the outset, analyses of the 2008 financial crisis, in mainstream as well as feminist discussions, have been gendered. In particular, rampant risk taking in an unregulated environment, widely deemed to be a principle cause of the crash, has been associated with masculine characteristics. In this article I explore how the concepts of gender and risk entwine in two films on the financial crisis – The Other Guys and Margin Call. By looking at how gender is used to dramatise financial risk, I explore how understandings of high risk behaviour are gendered, and the implications this has in the context of finance. Fictional representations mediate public understanding of this notoriously complex field, as the number of films and documentaries on the crisis demonstrates. Exploring how gender is used to communicate risk reminds us that risk taking is part of a performance of masculinity that needs to be established by constructing a feminine, risk-averse other. The contention of this paper is that to address gender bias in finance and the economy, gendered meanings of risk need to be openly challenged, and cultural and material analyses of gendered inequality brought into dialogue

Bacterivory by phototrophic picoplankton and nanoplankton in Arctic waters

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in FEMS Microbiology Ecology 82 (2012): 242–253, doi:10.1111/j.1574-6941.2011.01253.x.Mixotrophy, the combination of phototrophy and heterotrophy within the same individual, is widespread in oceanic systems. Yet, neither the presence nor ecological impact of mixotrophs has been identified in an Arctic marine environment. We quantified nano- and picoplankton during early autumn in the Beaufort Sea and Canada Basin and determined relative rates of bacterivory by heterotrophs and mixotrophs. Results confirmed previous reports of low microbial biomass for Arctic communities in autumn. The impact of bacterivory was relatively low, ranging from 0.6 x 103 to 42.8 x 103 bacteria mL-1 day-1, but it was often dominated by pico- or nano-mixotrophs. From 1-7% of the photosynthetic picoeukaryotes were bacterivorous, while mixotrophic nanoplankton abundance comprised 1-22% of the heterotrophic and 2-32% of the phototrophic nanoplankton abundance, respectively. The estimated daily grazing impact was usually < 5% of the bacterial standing stock, but impacts as high as 25% occurred. Analysis of denaturing gradient gel electrophoresis band patterns indicated that communities from different depths at the same site were appreciably different, and that there was a shift in community diversity at the midpoint of the cruise. Sequence information from DGGE bands reflected microbes related to ones from other Arctic studies, particularly from the Beaufort Sea.Funding for participation in the 2008 cruise was provided by the Woods Hole Oceanographic Institution Arctic Research Initiative, with additional support from National Science Foundation Grants OPP-0838847 (RWS) and OPP-0838955 (RJG)

Adjuvant treatment with anti-PD-1 in acral melanoma:A nationwide study

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM

Adjuvant treatment with anti-PD-1 in acral melanoma:A nationwide study

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM. </p

Adjuvant treatment with anti-PD-1 in acral melanoma:A nationwide study

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM. </p

Cost-effectiveness of treatment sequences for BRAF-mutant advanced melanoma in the Netherlands using a health economic model

BACKGROUND: This study aims to evaluate the cost-effectiveness of treatment sequences for patients with advanced melanoma with a BRAF mutation in the Netherlands from a societal perspective.METHODS: A semi-Markov model with a life-time horizon has been used to evaluate cost-effectiveness of 21 treatment sequences. Real-world data from the Dutch Melanoma Treatment Registry (DMTR) were used to estimate time to progression, next treatment and death. Utilities by health state as well as hospital costs, health care costs outside the hospital, patient and family costs and productivity costs were also derived from the DMTR. Drug costs were estimated based on the recommended dose and duration of treatment. Incremental cost-effectiveness ratios (ICERs) were presented as incremental costs per QALY gained.RESULTS: Health benefits of treatment sequences consisting of targeted therapies and immunotherapies vary between 2.3 and 5.8 QALYs gained per patient when compared to chemotherapy. The increase in costs varies between €112,000 and €383,000. The efficiency frontier consists of nivolumab in the first line followed by ipilimumab in the second line (ICERs of €42,000/QALY and €44,000/QALY), nivolumab in the first line followed by encorafenib plus binimetinib in the second line (ICERs of €71,000/QALY and €68,000/QALY) and nivolumab plus ipilimumab in the first line followed by encorafenib plus binimetinib in the second line (ICERs of €74,000/QALY and €76,000/QALY). The first treatment given within a sequence as well as assumptions regarding treatment duration have a substantial impact on cost-effectiveness outcomes.CONCLUSION: The ICERs can be considered cost-effective at different cost-effectiveness thresholds.</p

Development of a Decision Model to Estimate the Outcomes of Treatment Sequences in Advanced Melanoma

BACKGROUND: A decision model for patients with advanced melanoma to estimate outcomes of a wide range of treatment sequences is lacking.OBJECTIVES: To develop a decision model for advanced melanoma to estimate outcomes of treatment sequences in clinical practice with the aim of supporting decision making. The article focuses on methodology and long-term health benefits.METHODS: A semi-Markov model with a lifetime horizon was developed. Transitions describing disease progression, time to next treatment, and mortality were estimated from real-world data (RWD) as a function of time since starting treatment or disease progression and patient characteristics. Transitions were estimated separately for melanoma with and without a BRAF mutation and for patients with favorable and intermediate prognostic factors. All transitions can be adjusted using relative effectiveness of treatments derived from a network meta-analysis of randomized controlled trials (RCTs). The duration of treatment effect can be adjusted to obtain outcomes under different assumptions.RESULTS: The model distinguishes 3 lines of systemic treatment for melanoma with a BRAF mutation and 2 lines of systemic treatment for melanoma without a BRAF mutation. Life expectancy ranged from 7.8 to 12.0 years in patients with favorable prognostic factors and from 5.1 to 8.7 years in patients with intermediate prognostic factors when treated with sequences consisting of targeted therapies and immunotherapies. Scenario analyses illustrate how estimates of life expectancy depend on the duration of treatment effect.CONCLUSION: The model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects and the transitions influenced by treatment can be adjusted. We show how using RWD and data from RCTs can harness advantages of both data sources, guiding the development of future decision models.HIGHLIGHTS:The model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects as well as the transitions that are influenced by treatment can be adjusted.The long-term health benefits of treatment sequences depend on the place of different therapies within a treatment sequence.Assumptions about the duration of relative treatment effects influence the estimates of long-term health benefits.We show how the use of real-world data and data from randomized controlled trials harness the advantages of both data sources, guiding the development of future decision models.</p

Response to immune checkpoint inhibitors in acral melanoma:A nationwide cohort study

Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM). Methods: We included patients with advanced AM and CM treated with first-line anti-programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression-free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS. Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8–5.6) than patients with CM (10.1 months; 95%CI: 8.5–12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26–2.11; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15–2.06; P = 0.004) than CM. Conclusions: This study shows lower effectiveness of anti-PD -1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies